Process for making quinoxaline-di-n-oxides

ABSTRACT

A NOVEL PROCESS CONSISTING OF THE REACTION BETWEEN AN O-QUINONEDIOXIME AND A REAGENT SUCH AS AN A-DICARBONYL COMPOUND, AN A-HYDROXYCARBONYL COMPOUND, AN A-HALOCARBONYL COMPOUND, AN A-EPOXYCARBONYL OR AN A-EPOXY HALIDE.

United States Patent 3,553,208 PROCESS FOR MAKING QUINOXALINE-DI-N-OXIDES' Eli Abushanab, Groton, Conn., assignor to Chas. Pfizer &Co., Inc., New York, N.Y., a corporation of Delaware No Drawing. FiledJuly 5, 1968, Ser. No. 742,513

Int. Cl. C07d 51/78 US. Cl. 260250 14 Claims ABSTRACT OF THE DISCLOSUREA novel process consisting of the reaction between an o-quinonedioximeand a reagent such as an a-dicarbonyl compound, an a-hydroxycarbonylcompound, an u-halocarbonyl compound, an u-epoxycarbonyl compound or anu-epoxy halide.

BACKGROUND OF THE INVENTION This invention relates to a novel syntheticprocedure and, more particularly, to a novel method for the preparationof quinoxaline-di-N-oxides. The compounds prepared by the novel subjectprocess are useful in the control of various pathogenic microorganisms,QuinoXaline-di-N- oxides in general are known to possess gram-negativeantibacterial activity. For instance, several quinoxalinedi-N-oxidesbearing 2-alkyl or 2,3-dialkyl groups has been described by Lundquist etal., US. Pat. 2,626,259 issued I an. 20, 1953, and by Wiedling, ActaPathol, et Microbiol. Scand. 22, 379-91 (1945). Mcllwain, J. Chem. Soc.322 (1943) and King et al., J. Chem. Soc. 3012 (1949), disclose theantibacterial activity of Z-methyl 3 n amylquinoxaline-di-N-oxide and ofseveral 6-substituted quinoxaline-di-N-oxides, respectively.

SUMMARY OF THE INVENTION Accordingly, a general organic synthetic methodis disclosed for the preparation of the subject compounds whichcomprises reacting an o-quinonedioxime with the following reagents shownherein below to provide the indicated products:

wherein Y can be hydrogen and other simple substituents usually found onbenzene rings, that is, alkyl, alkoxy, halo, etc. and R and R are eachhydrogen or alkyl of from 1 to 12 carbon atoms, n is an integer from 2to 18, X is hydrogen, hydroxy, mercapto, amino, alkyloxy andalkylsulfonyl, said alkyl groups containing from 1 to 4 carbon atoms, Inis an integer from 2 to 12 hal is a halogen atom and p is an integerfrom 2 to 12.

It should be noted that this is a basic reaction which takes placebetween an o-quinonedioxime with the reagents shown above. That is tosay, the type of o-quinonedioxime, whether substituted or not, will haveno effect on the overall reaction sequence and will only determine thetype of final product obtained.

DETAILED DESCRIPTION OF THE INVENTION Concerning the o-quinonedioximereagent also known as o-benzoquinone-dioxime, it is found thatsubstituted derivatives will work equally as well as o-quinonedioxirneitself. Thus, o-quinonedioxime or a substituted o-quinonedioxime may beemployed in the process of the present invention. Such compounds areeither readily available or easily prepared by one skilled in the art.One simple means for obtaining such derivatives is by a reduction of thecorresponding isobenzofuroxan. A review article entitled The Furoxans byJ. V. R. Kaufman and J. P. Picard in Chemical Reviews, vol. 59, page 448(1959) refers to the preparation of many substituted isobenzofuroxanswhich can then be reduced to prepare the starting reagents of the hereindisclosed process.

With respect to the other reagent used in the herein disclosed process,there are five categories of reagents which are found to be suitable andapplicable to the process of this invention. Namely, they areot-dicarbonyl compounds, oc-hYCllOXYCflI'bOlWl compounds, a-halocarbonylcompounds, a-epoxycarbonyl compounds and otepoxy halides. Thesecategories are depicted in the reaction sequences shown above. Despitethe fact that this 3 reaction is general and basic for these particularreagents, the products themselves, that is the resultingquinoxalinedi-N-oxide, will have substituents on the quinoxaline nucleusdependent on the nature of the second reagent. For example, a non-cyclica-dicarbonyl compound will provide a 2,3-dialkylquinoxaline-di-N-oxide.On the other hand, an alkyl ot-ketoaldehyde will give rise to 2-alkyl,3-hydroxyquinoxaline di N-oxide. In like manner, an alkyl ot-epoxyhalide will provide a 2-alkyl3-hydroxymethylquinoxaline-di-N-oxide.

It is therefore apparent by simple inspection that the product which oneobtains as well as the ultimate position of the substituent coming fromthe second reagent is dependent upon the particular carbonyl-containingcompound (second reagent) utilized.

As for the inclusion of a solvent in the basic process of thisinvention, this will not be a critical factor and its desirability willdepend on many factors. For instance, if a sizable amount of liquidamine is used, there may not be any need to use a solvent. If, however,the reactants when combined produce a viscous system, it is highlydesirable to include an appropriate solvent. For purposes of thisinvention, an appropriate solvent is any solvent which does not react inan undesired way with either of the reactants or the final products. Oneof the advantages in including a solvent is that when certain refluxtemperatures are desired, by choosing the appropriate solvent, thedesired elevated reaction temperature can be attained. Re actiontemperatures do not appear to be critical in the present processalthough it is generally preferred to carry out the reaction attemperatures above room temperatures. A preferred range is from about 30C. to about 100 C. Temperatures below 30 C. may be employed, forinstance, 0 C. to 30 C., but are less preferred.

With regard to the isolation of the desired products of this invention,it is found in many instances that in the course of or upon completionof reaction the product precipitates out in crystalline form. In suchcases, all that is required is filtration, washing and drying. If, onthe other hand, the product does not completely precipitate or if itremains in solution, the reaction workup consists of evaporating themixture almost to dryness and then filtering the product. If the sodiumsalt of the product forms, as it does in certain instances, the generalprocedure consists of filtering said salt, dissolving it in water,acidifying the solution and subsequently filtering the product whichforms. All of the above techniques are well known to trained techniciansworking in the organic laboratory.

The vertification that the herein disclosed compounds are effectiveantimicrobial agents is established by experimental evaluations. Onesuch in-vitro evaluation consists of seeding nutrient broth containingvarious concentrations of the subject compounds with a particularorganism and subsequently determining the minimum concentration of theantimicrobial test compound (in micrograms/ milliliter) at which growthof the microorganism failed to occur. For instance, the following isonly a representative list of compounds disclosed herein which haveexhibited in-vitro activity in the above described procedure:

Z-methylquinoxaline-di-N-oxide 2,3-dimethylquinoxaline-di-N-oxide2-methyl-3-hydroxyquinoxaline-di-N-oxide Illustrative MIC values areshown in the examples. It should be understood that these are onlyrepresentative illustrations and are provided to show typical desirableresults.

Since all of the products of the present invention possess in vitroactivity against harmful microorganisms, they are useful as industrialantimicrobials, for instance, watertreatment, slime-control, paintpreservation, wood preservation, etc., as well as for topicalapplication purposes, for example disinfectants, etc. In the latterapplication, it will often be convenient to compound the selectedprodnot with a pharmaceutically-acceptable carrier for ease inapplication. Thus, for example, they may be blended with vegetable ormineral oils or incorporated in emollient creams. Similarly, they may bedissolved or dispersed in liquid carriers or solvents such as water,alcohol, glycols or mixtures thereof or other reaction-inert media, thatis media which have no harmful effect on the active ingredient. For suchpurposes, it will generally be acceptable to employ concentrations ofactive ingredients of from about 0.01% to about 10% by weight based ontotal composition.

Furthermore, the showing of in vitro antimicrobial activity findsparticular utility in the growth promotion of animals in the control ofchronic respiratory disease in poultry, infectious sinusitis in turkeys,and urinary tract and systemic and non-systemic infections in animals,including man.

The following examples are given to illustrate further the scope of thepresent invention, but should not be interpreted as limiting the scopethereof.

EXAMPLE I 2,3-dimethylquinoxaline-di-N-oxide A mixture containingo-quinonedioxime (1.38 g., 0.01 M), diacetyl (1.46 g., 0.01 M) and 30ml. of tetrahydrofuran is allowed to reflux on a steam bath overnight.The solid product which precipitates is filtered and recrystallized froma chloroform-hexane (1:1 mixture), melting point 190-192" C.

EXAMPLE II The procedure of Example I is repeated wherein stoichiometricequivalent amounts of the a-diketones shown herein below are used inplace of diacetyl to provide the indicated products in good yields:

hydrofuran 40 ml. is stirred at room temperature overnight. The productwhich precipitates is filtered and recrystallized from methanol to yieldthe desired product having a melting point 231232 C.

Analysis.-Calc. for C 'H N O (percent) C, 56.25; H, 4.20; N, 14.55.Found (percent): C, 56.77; H, 4.44; N, 14.44.

EXAMPLE IV The procedure of Example HI is repeated whereinstoichiometric equivalent amounts of the a-ketoaldehydes shown hereinbelow are used in place of pyruvaldehyde to provide the productsindicated in good yields:

RCCH I! ll 0 a-Ketoaldehyde R: Product C H2-ethyl-3-hydroxyquinoxaline-di-N- oxide. n-C H2-n-'butyl-3-hydroxyquinoxaline-di-N- oxide. n-C H2-n-hexyl-3-hydroxyquinoxaline-di-N- oxide. n-C H2-n-dodecyl-3-hydroxyquinoxaline-di- N-oxide.

EXAMPLE V Z-hydroxyquinoxaline-di-N-oxide A mixture containingo-quinone-dioxime (1.38 g., 0.01 mol), glyoxal (2 ml. of a aqueoussolution) and 400 stoichiometric equivalent amounts of -theot-hydroxycarbonyl compounds listed herein below are used in place ofacetol to provide the indicated products in good yields:

ml. of tetrahydrofuran allowed to stand overnight. The reaction mixtureis then evaporated almost to dryness, acetone (25 ml.) is added and thesolid product is filtered. The desired product has a melting point of240-245 C.

Analysis.Calc. for C H N O (percent): C, 53.93; H, 3.37; N, 15.17. Found(percent): C, 53.82; H, 3.37; N, 15.37.

EXAMPLE VI 2,3-tetramethylenequinoxaline-di-N-oxide 'A mixturecontaining o-quinonedioxime (1.38 g., 0.01 M), cyclolrexane-1,2-dione(1.12 g., 0.01 M) and ml. of tetrahydrofuran is allowed to stand overnight. The resulting mixture is evaporated to dryness and the solidproduct is collected, washed and dried to provide the desired product.

EXAMPLE VII The procedure of Example VI is repeated whereinstoichiomet-ric equivalent amounts of the cyclic a-diketones listedherein below are used in place of cyclohexane- 1,2-dione to provide theproducts indicated in good yields:

Cyclic a-diketone: Product n=3 2,3-trimethylenequinoxaline-di N-oxide.n=8 2,3-octamethylenequinoxaline-di-N oxide.

21:10-..- 2,3-decamethylenequinoxaline-di-N-oxide. 11:18-..-2,3-bctadecylmethylenequinoxalinedi-N-oxide.

EXAMPLE VIII 2-methylquinoxalline di-N-oxide A mixture containingo-quinonedioxime (1.38 g., 0.1 M), acetol (0.01 M) and 20 ml. oftetrahydrofuran is allowed to stand overnight. The solid precipitate isfiltered, washed and dried to yield the desired product having a meltingpoint 178 l79 C.

EXAMPLE IX The procedure of Example VIII is repeated wherein EXAMPLE XQuinoxaline-di-N-oxide A mixture containing o-quinone-dioxime (1.38 g.,0.01 M), glycoaldehyde (0.6 g., 0.01 M) and 20 m1. of tetrahydrofuran isallowed to stir at room temperature overnight. The precipitate whichforms is filtered, washed and recrystallized from a chloroform-hexanemixture to give the desired product having a melting point 221- 223 C.(MIC against P. vulgaris is 12.5 meg/m1.)

EXAMPLE XI 2-hydroxymethylquinoxaline-di-N-oxide A mixture containingo-quinonedioxime (6.8 g., 0.05 M), 1,3 dihydroxy acetone (4.5 g., 0.05M) and ml. of methanol is stirred and refluxed for 18 hours. Thereaction mixture is then evaporated almost to dryness and the solidprecipitate is filtered. Recrystallization from methanol yields thedesired product having a melting point 198l99 C.

EXAMPLE XII The procedure of Example I is repeated wherein the followingsugars having the a-hydroxycarbonyl configuration listed herein below,in stoichiometric equivalent amounts, are used in place of diacetyl toprovide the products indicated in good yields:

Sugar: Product Fructose 2-(1,2,3,4-tetrahydroxybutyl)quinoxaline-di-N-oxide. Tagatose 2-(1,2,3,4-tetrahydroxybutyl)quinoxaline-di-N-oxide. Glucose 2-( 1,2,3-trihydroxypropyl)quinoxaiine-di-N-oxide.

EXAMPLE XIII The procedure of Example I is repeated whereinstoichiomet'ric equivalent amounts of the a-halocarbonyl compoundslisted herein below are used in place of diacetyl to provide theproducts indicated in good yields:

a-Halocarbonyl compound Product 2-ethylquinoxaline-di-N-oxide.

2-(hydroxyethyl) quinoxaline-di-N-oxide. 2-(6-thiohexyl)quinoxaline-di-N-oxide. 2-(8-aminoocty1) quinoxaline-di-N-oxide.2-(4-methoxybutyl) quinoxaline-di-N-oxide. 2-(10-butoxydecyl)quinoxaline-di-Noxide. 2-(2-methy1sulfonyleth yl) quinoxaline-di-N-oxide2-(3-butylsulfonylpropyl) quinoxaline-di-N-oxide.2-butyl-3-methylquinoxaline-di-N-oxide.2-hydroxyethyl-3-buty1quinoXaline-di-N-oxide.

mmmmmmmm wherein Y is hydrogen, alkyl, alkoxy or halo with a reagentselected from the group consisting of:

7 EXAMPLE XIV The procedure of Example I is repeated whereinstoichiometric equivalent amounts of the a-epoxycarbonyl compoundslisted herein below are used in place of diacetyl to provide theproducts indicated in good yields: 5

a-Epoxycarbonyl compound Product2-propyl-3-hydroxymethylquinoxaline-di-N0xide.Z-ethyI-S-hydroxymethylquinoxaline-di-N-oxide.2-heXyl-3-hydroxymethylquinoxaline-diN-oxide.2-dodecyl-3-hydroxymethylquinoxaline-di-N-oxide.Q-(g-lgdroxyethyl)-3-hydroxymethylquinoxaline- 1- -0X e.2-(2-thioethyl)-3hydroxymethylquinoxaline-di-N- 1 1 m momma b wherein Rand R are each selected from tne group consisting of hydrogen and alkylcontaining from 1 to 12 carbon atoms EXAMPLE XV 3 The procedure ofExample I is repeated wherein stoichiometric equivalent amounts of thea-epoxyhalides listed herein below are used in place of diacetyl to pro-N vide the products indicated in good yields: (OHM (IJ O lialCI-I2OH-CHRl wherein R is as aforesaid and n is an integer of from 2 to 18-a-Epoxyhalide compound (0) 1'12 Product X(CH2)mCCHOH2-hydr0xymethylquinoxaline-di-N-oxidc. H 2-(a-hydroxyethyl)uinoxaline-di-N-oxide. 0 2-(a-hydroxypropyl quinoxaline-dLN-oxide.

2-(a-hydroxypentyl)quinoxaline-di-Npxide.

mwhydmxydecyl)quinoxanne di N oxide wherein X is selected from the groupconsisting of hydrogen, hydroxy, mercapto, amino and alkoxy and alkylcontaining from 1 to 4 carbon atoms, R is selected from the groupconsisting of hydrogen and alkyl containing from 1 to 4 carbon atoms andm' is zero when X is hydrogen or otherwise is an integer of from 2 to12;

(d) 1,3-dihydroxyacetone;

(e) a-hydroxycarbonyl containing sugar,

EXAMPLE XVI Dioxime .3-ethyl-o-quinonedioxime.

3 methoxy-o-qui- 5-ethyl-2,3 -dimethylquinoxa- 5methoxy-2,3-dimethylqui- Product line-di-N-oxide.

wherein X and R are as aforesaid, p is an integer from nonedioxime.noxaline-di-N-oxide. 3-br0mo-o-quinone- S-bromo 2,3 dimethylqui- 2 to 12and Hal 1S halogen;

dioxime. IlOXflllnC-dl-N-OXldfi. (s) 2)i What is claimed is: E, 1. Aprocess for preparing a quinoxaline-di-N-oxide WhereinR X and are asaforesaid and which comprises reacting an o-quinonedioxime of the pformula: 7 (h) wherein R and Hal are as aforesaid.

2. The process oi claim 1 wherein said selected reagent 3. The processof claim 2 wherein R is methyl and R is hydrogen.

4. The process of claim 1 wherein said selected reagent is (b).

5. The process of claim 1 wherein said selected reagent is (c).

6. The process of claim 5 wherein X is mercapto, R is hydrogen and m. is2.

7. The process of claim 1 wherein said selected reagent is (d).

8. The process of claim 1 wherein said selected reagent is (e).

9. The process of claim 8 wherein said reagent (e) is selected from thegroup consisting of fructose, tagatose and glucose.

10. The process of claim 1 wherein said selected reagent is (f).

11. The process of claim 1 wherein said selected reagent is (g).

12. The process of claim 11 wherein each of X and R is hydrogen and p is2.

13. The process of claim 1 wherein said selected reagent is (h).

14. The process of claim 13 wherein Hal is chlorine and R is hydrogen.

References Cited UNITED STATES PATENTS 3,260,720 7/1966 Berndt 260250NICHOLAS S. RIZZO, Primary Examiner US. Cl. X.R. 424-250 UNITED STATESPATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 35532O8 Dated January1971 Inventor 5) E11 Abushanab It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Col. 2, line 30, "(G)ha1 CH2-CI\{-/CH-R should read (G) hal-CH -CH-CH-RCol. 6, line 61, that portion of the formula reading "-ha" shmread -halCol. 7, line 72, "-N-OH" should read =N-OH Signed and sealed this 29thday of June 1971 (SEAL) Attest:

EDWARD M.FLETCHER,JR. Attesting Officer WILLIAM E. SGHUYLER, JRCommissioner of Patents

